肿瘤外泌体介导的miR-24激活脂肪线粒体UCP1促进白色脂肪褐色化的机制研究

Cancer-associated cachexia is one of the most important reasons which leads to the death of patients. Recent researches show that a phenotypic switch from white adipose tissue (WAT) to brown adipose tissue (BAT), a phenomenon termed WAT browning, takes place in cancer-associated cachexia. UCP1 is specifically expressed in BAT and is the crucial protein which determines the function of BAT. WAT browning is associated with increased expression of UCP1. Previous studies show that exosomes can mediate communication between different cells by transferring RNA、DNA or protein. In this study, we found that the exosomes secreted by gastric cancer cells can transport into fat cells and regulate adipose tissue browning. Microarray sequencing, Bioinformatics prediction and in vitro study suggested that miR-24, which was enriched in exosomes secreted by gastric cancer cells, could regulate UCP1 by targeting NR1D1. We plan to demonstrate that exosome-derived miR-24 can be transported into fat cells and upregulates UCP1 by clinical, in vitro and in vivo studies. By illuminating this new mechanism of gastric cancer associated cachexia, we expect to propose a potential new target for cachexia treatment.

代谢紊乱等恶病质是导致肿瘤患者最终死亡的重要原因之一，最新的研究表明白色脂肪褐色化在肿瘤恶病质的形成中发挥了重要作用。UCP1特异性地分布在褐色脂肪组织中，是褐色脂肪发挥功能的决定性蛋白，白色脂肪的褐色化也伴随着UCP1表达水平的上升。近年来的研究表明，外泌体可以运输RNA、DNA、蛋白等多种物质介导细胞间的信号传递。在本课题的前期结果中，我们发现胃癌外泌体能够融合进入脂肪细胞，调控脂肪细胞的转化及代谢能力。高通量测序、生物信息学预测以及细胞学实验表明胃癌外泌体中高表达的miR-24能够调控脂肪细胞中UCP1的上游基因NR1D1。我们计划通过临床筛查、体外及体内实验证明胃癌外泌体miR-24能够转运至脂肪细胞，通过调控NR1D1促进UCP1的表达，进而诱导白色脂肪的褐色化，增加机体的耗能和代谢速率，阐明胃癌患者恶病质发生的一种新机制，为肿瘤患者恶病质的治疗提供潜在的新靶标。

代谢紊乱等恶病质是导致肿瘤患者最终死亡的重要原因之一，最新的研究表明白色脂肪褐.色化在肿瘤恶病质的形成中发挥了重要作用。UCP1特异性地分布在褐色脂肪组织中，是褐色脂.肪发挥功能的决定性蛋白，白色脂肪的褐色化也伴随着UCP1表达水平的上升。近年来的研究表.明，外泌体可以运输RNA、DNA、蛋白等多种物质介导细胞间的信号传递。在本课题的前期结果.中，我们发现胃癌外泌体能够融合进入脂肪细胞，调控脂肪细胞的转化及代谢能力。高通量测.序、生物信息学预测以及细胞学实验表明胃癌外泌体中高表达的miR-24能够调控脂肪细胞中UC.P1的上游基因NR1D1。我们计划通过临床筛查、体外及体内实验证明胃癌外泌体miR-24能够转.运至脂肪细胞，通过调控NR1D1促进UCP1的表达，进而诱导白色脂肪的褐色化，增加机体的耗.能和代谢速率，阐明胃癌患者恶病质发生的一种新机制，为肿瘤患者恶病质的治疗提供潜在的.新靶标。